Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Irit Reichenstein; Chen Eitan; Sandra Diaz-Garcia; Guy Haim; Iddo Magen; Aviad Siany; Mariah L. Hoye; Natali Rivkin; Tsviya Olender; Beata Toth; Revital Ravid; Amitai D. Mandelbaum; Eran Yanowski; Jing Liang; Jeffrey K. Rymer; Rivka Levy; Gilad Beck; Elena Ainbinder; Sali M.K. Farhan; Kimberly A. Lennox; Nicole M. Bode; Mark A. Behlke; Thomas Möller; Smita Saxena; Cristiane A.M. Moreno; Giancarlo Costaguta; Kristel R. van Eijk; Hemali Phatnani; Ammar Al-Chalabi; A. Nazli Başak; Leonard H. van den Berg; Orla Hardiman; John E. Landers; Jesus S. Mora; Karen E. Morrison; Pamela J. Shaw; Jan H. Veldink; Samuel L. Pfaff; Ofer Yizhar; Christina Gross; Robert H. Brown; John M. Ravits; Matthew B. Harms; Timothy M. Miller; Eran Hornstein

doi:10.1126/scitranslmed.aav5264

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Irit Reichenstein, Chen Eitan, Sandra Diaz-Garcia, Guy Haim, Iddo Magen, Aviad Siany, Mariah L. Hoye, Natali Rivkin, Tsviya Olender, Beata Toth, Revital Ravid, Amitai D. Mandelbaum, Eran Yanowski, Jing Liang, Jeffrey K. Rymer, Rivka Levy, Gilad Beck, Elena Ainbinder, Sali M.K. Farhan, Kimberly A. LennoxNicole M. Bode, Mark A. Behlke, Thomas Möller, Smita Saxena, Cristiane A.M. Moreno, Giancarlo Costaguta, Kristel R. van Eijk, Hemali Phatnani, Ammar Al-Chalabi, A. Nazli Başak, Leonard H. van den Berg, Orla Hardiman, John E. Landers, Jesus S. Mora, Karen E. Morrison, Pamela J. Shaw, Jan H. Veldink, Samuel L. Pfaff, Ofer Yizhar, Christina Gross, Robert H. Brown, John M. Ravits, Matthew B. Harms, Timothy M. Miller, Eran Hornstein

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1 Scopus citations

Abstract

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

Original language	English
Article number	eaav5264
Journal	Science translational medicine
Volume	11
Issue number	523
DOIs	https://doi.org/10.1126/scitranslmed.aav5264
State	Published - Dec 18 2019

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Reichenstein, I., Eitan, C., Diaz-Garcia, S., Haim, G., Magen, I., Siany, A., Hoye, M. L., Rivkin, N., Olender, T., Toth, B., Ravid, R., Mandelbaum, A. D., Yanowski, E., Liang, J., Rymer, J. K., Levy, R., Beck, G., Ainbinder, E., Farhan, S. M. K., ... Hornstein, E. (2019). Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology. Science translational medicine, 11(523), [eaav5264]. https://doi.org/10.1126/scitranslmed.aav5264

Reichenstein, Irit ; Eitan, Chen ; Diaz-Garcia, Sandra ; Haim, Guy ; Magen, Iddo ; Siany, Aviad ; Hoye, Mariah L. ; Rivkin, Natali ; Olender, Tsviya ; Toth, Beata ; Ravid, Revital ; Mandelbaum, Amitai D. ; Yanowski, Eran ; Liang, Jing ; Rymer, Jeffrey K. ; Levy, Rivka ; Beck, Gilad ; Ainbinder, Elena ; Farhan, Sali M.K. ; Lennox, Kimberly A. ; Bode, Nicole M. ; Behlke, Mark A. ; Möller, Thomas ; Saxena, Smita ; Moreno, Cristiane A.M. ; Costaguta, Giancarlo ; van Eijk, Kristel R. ; Phatnani, Hemali ; Al-Chalabi, Ammar ; Başak, A. Nazli ; van den Berg, Leonard H. ; Hardiman, Orla ; Landers, John E. ; Mora, Jesus S. ; Morrison, Karen E. ; Shaw, Pamela J. ; Veldink, Jan H. ; Pfaff, Samuel L. ; Yizhar, Ofer ; Gross, Christina ; Brown, Robert H. ; Ravits, John M. ; Harms, Matthew B. ; Miller, Timothy M. ; Hornstein, Eran. / Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology. In: Science translational medicine. 2019 ; Vol. 11, No. 523.

@article{e5c52d9777d845c4b5fff1d4ceec652d,

title = "Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology",

abstract = "Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.",

author = "Irit Reichenstein and Chen Eitan and Sandra Diaz-Garcia and Guy Haim and Iddo Magen and Aviad Siany and Hoye, {Mariah L.} and Natali Rivkin and Tsviya Olender and Beata Toth and Revital Ravid and Mandelbaum, {Amitai D.} and Eran Yanowski and Jing Liang and Rymer, {Jeffrey K.} and Rivka Levy and Gilad Beck and Elena Ainbinder and Farhan, {Sali M.K.} and Lennox, {Kimberly A.} and Bode, {Nicole M.} and Behlke, {Mark A.} and Thomas M{\"o}ller and Smita Saxena and Moreno, {Cristiane A.M.} and Giancarlo Costaguta and {van Eijk}, {Kristel R.} and Hemali Phatnani and Ammar Al-Chalabi and Ba{\c s}ak, {A. Nazli} and {van den Berg}, {Leonard H.} and Orla Hardiman and Landers, {John E.} and Mora, {Jesus S.} and Morrison, {Karen E.} and Shaw, {Pamela J.} and Veldink, {Jan H.} and Pfaff, {Samuel L.} and Ofer Yizhar and Christina Gross and Brown, {Robert H.} and Ravits, {John M.} and Harms, {Matthew B.} and Miller, {Timothy M.} and Eran Hornstein",

year = "2019",

month = dec,

day = "18",

doi = "10.1126/scitranslmed.aav5264",

language = "English",

volume = "11",

journal = "Science Translational Medicine",

issn = "1946-6234",

number = "523",

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Reichenstein, I, Eitan, C, Diaz-Garcia, S, Haim, G, Magen, I, Siany, A, Hoye, ML, Rivkin, N, Olender, T, Toth, B, Ravid, R, Mandelbaum, AD, Yanowski, E, Liang, J, Rymer, JK, Levy, R, Beck, G, Ainbinder, E, Farhan, SMK, Lennox, KA, Bode, NM, Behlke, MA, Möller, T, Saxena, S, Moreno, CAM, Costaguta, G, van Eijk, KR, Phatnani, H, Al-Chalabi, A, Başak, AN, van den Berg, LH, Hardiman, O, Landers, JE, Mora, JS, Morrison, KE, Shaw, PJ, Veldink, JH, Pfaff, SL, Yizhar, O, Gross, C, Brown, RH, Ravits, JM, Harms, MB, Miller, TM & Hornstein, E 2019, 'Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology', Science translational medicine, vol. 11, no. 523, eaav5264. https://doi.org/10.1126/scitranslmed.aav5264

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology. / Reichenstein, Irit; Eitan, Chen; Diaz-Garcia, Sandra; Haim, Guy; Magen, Iddo; Siany, Aviad; Hoye, Mariah L.; Rivkin, Natali; Olender, Tsviya; Toth, Beata; Ravid, Revital; Mandelbaum, Amitai D.; Yanowski, Eran; Liang, Jing; Rymer, Jeffrey K.; Levy, Rivka; Beck, Gilad; Ainbinder, Elena; Farhan, Sali M.K.; Lennox, Kimberly A.; Bode, Nicole M.; Behlke, Mark A.; Möller, Thomas; Saxena, Smita; Moreno, Cristiane A.M.; Costaguta, Giancarlo; van Eijk, Kristel R.; Phatnani, Hemali; Al-Chalabi, Ammar; Başak, A. Nazli; van den Berg, Leonard H.; Hardiman, Orla; Landers, John E.; Mora, Jesus S.; Morrison, Karen E.; Shaw, Pamela J.; Veldink, Jan H.; Pfaff, Samuel L.; Yizhar, Ofer; Gross, Christina; Brown, Robert H.; Ravits, John M.; Harms, Matthew B.; Miller, Timothy M.; Hornstein, Eran.

In: Science translational medicine, Vol. 11, No. 523, eaav5264, 18.12.2019.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

AU - Reichenstein, Irit

AU - Eitan, Chen

AU - Diaz-Garcia, Sandra

AU - Haim, Guy

AU - Magen, Iddo

AU - Siany, Aviad

AU - Hoye, Mariah L.

AU - Rivkin, Natali

AU - Olender, Tsviya

AU - Toth, Beata

AU - Ravid, Revital

AU - Mandelbaum, Amitai D.

AU - Yanowski, Eran

AU - Liang, Jing

AU - Rymer, Jeffrey K.

AU - Levy, Rivka

AU - Beck, Gilad

AU - Ainbinder, Elena

AU - Farhan, Sali M.K.

AU - Lennox, Kimberly A.

AU - Bode, Nicole M.

AU - Behlke, Mark A.

AU - Möller, Thomas

AU - Saxena, Smita

AU - Moreno, Cristiane A.M.

AU - Costaguta, Giancarlo

AU - van Eijk, Kristel R.

AU - Phatnani, Hemali

AU - Al-Chalabi, Ammar

AU - Başak, A. Nazli

AU - van den Berg, Leonard H.

AU - Hardiman, Orla

AU - Landers, John E.

AU - Mora, Jesus S.

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Veldink, Jan H.

AU - Pfaff, Samuel L.

AU - Yizhar, Ofer

AU - Gross, Christina

AU - Brown, Robert H.

AU - Ravits, John M.

AU - Harms, Matthew B.

AU - Miller, Timothy M.

AU - Hornstein, Eran

PY - 2019/12/18

Y1 - 2019/12/18

N2 - Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

AB - Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

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U2 - 10.1126/scitranslmed.aav5264

DO - 10.1126/scitranslmed.aav5264

M3 - Article

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AN - SCOPUS:85080837788

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 523

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